Pharmacological and behavioral studies have shown that thyrotropin-releasing hormone (TRH) has a number of effects which are mediated directly in the CNS, and not via the pituitary. Among these is the ability to antagonize the depressant effects of a wide variety of chemically unrelated compounds, including alcohol, barbiturates, and benzodiazapines. Recent studies have implicated the cholinergic and/or GABAergic systems as possible mediators of this antogonism. Proposed are detailed neurochemical studies designed to: 1) elucidate the role of these transmitter systems in the CNS action of alcohol, barbiturates and TRH and to 2) investigate the hypothesis that the antagonism of drug induced depression by TRH may be the result of altering the functional balance between a cholinergically mediated arousal system and a GABAergically mediated suppression system. Because of the complicated nature of the cholinergic system, its function will be evaluated by measuring a number of parameters, including ACh turnover by two methods, high affinity choline-uptake and post-synaptic receptor sensitivity. These studies will also employ stereospecific micro-injections of TRH, and GABAergic and cholinergic agonists and antagonists into specific brain areas in an effort to further characterize the proposed neurochemical relationships. Clinical studies on the analeptic properties of TRH in man are also anticipated. Such studies should represent a major advance in understanding the action of depressant drugs, and might lead to the development of a new class of analeptic agents. The availability of such a drug, which could quickly and safely reverse the acute effects resulting from the use or abuse of alcohol, barbiturates and other depressants would have far reaching consequences in the treatment of drug overdose, in the management of intoxicated persons in a variety of situations, and in post-anesthesia recovery.